Correlations Between Severe Neonatal Intraventricular Hemorrhage and Neurodevelopmental Complications

MQP-BIO-DSA-1615 MQP-BIO-DSA-6822

CORRELATIONS BETWEEN SEVERE NEONATAL INTRAVENTRICULAR HEMORRHAGE AND NEURODEVELOPMENTAL COMPLICATIONS

A Major Qualifying Project Report

Submitted to the Faculty of the

WORCESTER POLYTECHNIC INSTITUTE

in partial fulfillment of the requirements for the

Degree of Bachelor of Science

Biology and Biotechnology

______Hannah Israel Kristin Newell

April 28, 2011

APPROVED:

______Robin Adair, Ph.D. David Adams, Ph.D. Developmental/Behavioral Pediatrics Biology and Biotechnology UMASS Medical Center WPI Project Advisor Major Advisor

ABSTRACT

Intraventricular hemorrhaging (IVH) is surprisingly common in premature infants, and may cause neurodevelopmental problems. However, demonstration of this correlation has been difficult to obtain at UMass Memorial Medical Center due to a communication disconnect between the Neonatal Intensive Care Unit where IVH is usually first diagnosed, and the Follow- up Clinic where subsequent developmental problems would be identified. To bridge this disconnect, standardized forms were developed to allow physicians to obtain medical follow-up data on infants. The results of a sample analysis of severe IVH show that severe IVH in premature infants born under 1000g correlates with neurodevelopmental problems such as cerebral palsy, cognitive impairment, and various sensory impairments.

TABLE OF CONTENTS

Signature Page ………………………………….……………………………………. 1

Abstract ………………………………………….…………………………………… 2

Table of Contents ………………………………………….…………………….…… 3

Acknowledgements ………………………………………………………………….. 4

Background ………………………………………………………………………….. 5

Project Purpose ………………………………………….…………………...………. 25

Methods …………………………………………….…………………………...…… 26

Results …………………………………………………………………………...….. 30

Discussion …………………………………………….…………………………...… 39

Bibliography ………………………………………………………………………… 42

Appendix ……………………………………..……………………………………... 53

ACKNOWLEDGEMENTS

We would like to thank UMass Memorial Medical Center, especially Robin Adair, MD and Alan Picarillo, MD, for sponsoring this project and for their help and guidance throughout our entire project. We would also like to thank Mary Naples for providing us with IS support throughout this project. Lastly, we would like to thank Professor David Adams for advising us on this project, and for all of his help in initiating and editing this project.

BACKGROUND

Vermont Oxford Network

The Vermont Oxford Network (VON) is a worldwide non-profit organization, consisting of 850 neonatal intensive care units. Yearly, VON acquires data on approximately 50,000 infants. VON is a voluntary service of health care professionals working to improve the safety and quality of newborn infants' medical care. The network holds an Annual Quality Congress of

Neonatology for all participating institutions (Vermont Oxford Network, 2011).

These health care professionals conduct numerous clinical trials, long-term follow-up studies, as well as outcome and epidemiologic research. This data is contained in a network database and is used to determine information about how newborn infant care influences their outcomes. The results of these studies are published by the network in scientific articles, peer reviewed medical journals, network publications, and on their website (Vermont Oxford

Network, 2011).

The VON database contains information on very low birth weight (VLBW) infants as well as others that fit their requirements. VON is able to take information from the database from the participating hospitals and provide an analysis and report confidentially on those hospitals.

This allows hospitals to see which areas can be improved for quality assurance purposes

(Vermont Oxford Network, 2011). Quality assurance opportunities are also available through collaboration with other hospitals through face-to-face contact or through web-based conferences

(Vermont Oxford Network, 2011).

Prematurity

Infants born before 37 weeks gestation are considered premature. The more preterm an

infant is born, the greater the risk that the infant will experience complications of prematurity.

High rates of morbidity and mortality in preterm infants can be attributed to complications

associated with prematurity. Approximately one third of infant deaths can be associated with

prematurity. Extremely premature infants have a mortality rate around 50 percent (the highest of

any gestational age group), as well as having the greatest risk of morbidity in the long-term.

Prematurity accounts for 25 percent of children with hearing or cognitive impairments, 35

percent of those with visual impairments, and 45 percent of children with cerebral palsy

(Eichenwald & Stark, 2008).

Three standard subdivisions classify underweight infants and three are designated for the

degree of immaturity (approximate gestational age at birth). Infants born weighing less than 1000

g are considered to be extremely low birth weight (ELBW). An infant born weighing between

1000 g and 1500 g is considered to be very low birth weight (VLBW). Infants born weighing

between 1500 g and 2500 g are considered to be low birth weight (LBW) (WHO, 2011). An

infant born before 25 weeks gestation is referred to as being extremely preterm (Nicolas et al.,

2000). Infants born between 25 and 32 weeks gestation is referred to as being very preterm. An

infant born from 32 to less than 37 weeks gestation is referred to as being late preterm (Pamela et

al., 2004).

Major NICU Advancements

Advancements in antenatal medicine and neonatal care have improved the rates of

preterm infant survival. However, this improved rate of survival was not followed by

6 proportional decreases in neurological disabilities (Stephens and Vohr, 2010). Three major advancements in neonatology contributing to this increased survival of preterm infants are the implementation of antenatal steroids, surfactant therapy, and high frequency oscillation ventilator use.

Antenatal Steroids

Antenatal steroids are a type of steroid administered intramuscularly to mothers when her baby is between 24 and 34 weeks gestation and is at risk for premature birth. Treatment consists of two doses of 12 mg of betamethasone or four doses of 6 mg dexamethasone. Antenatal steroids are the most effective 24 hours after administration, and the effects last for seven days.

Antenatal corticosteroids, administered to pregnant women, cross the placenta to induce cellular differentiation. Increased cellular differentiation results in significant reductions in neonatal mortality, respiratory distress syndrome (RDS), and intraventricular hemorrhage (IVH) (Norwitz et al., 2010).

Antenatal steroids aid fetal brain development by supporting the maturation of the germinal matrix microvasculature and reducing blood-brain barrier permeability. This increases the brain's resistance to stress, decreasing the risk of IVH (Stonestreet et al., 1998).

Corticosteroids are essential to fetal lung development. During late gestation, the concentration of circulating corticosteroids increases as the lungs mature (Ballard and Ballard,

1995). Infants born preterm miss this increase in corticosteroids. Fetuses exposed to antenatal steroid treatment have increased alveolar volume, closer alignment of alveoli to vessels, and thinner alveolar walls compared with non exposed fetuses of a similar gestational age. This leads

7 to better gas exchange and an enhanced response to postnatal surfactant treatment (Bonanno and

Wapner, 2009).

Surfactant Therapy

Surfactant is a lipoprotein complex, found in the lungs, which reduces alveolar collapse by forming a layer between the alveolar surface and the alveolar gas in the lungs, reducing surface tension (Berry, 1991). Very premature infants are often not able to produce their own surfactant because their type II alveolar epithelial cells, where surfactant is produced, have not matured. Without surfactant, the alveoli may not inflate or collapse on expiration, which can lead to respiratory distress syndrome (RDS) (Berry, 1991). Exogenous surfactant is the primary life- saving therapy for RDS in preterm infants (Ramanathan, 2009). There are two strategies for surfactant administration; prophylactic (or preventative) treatment, and rescue or therapeutic treatment (Ramanathan, 2009).

High Frequency Oscillation Ventilator

High frequency oscillatory ventilation (HFOV) is a mechanical ventilator that uses constant distending pressure, with pressure variations oscillating around the mean airway pressure. This ventilation strategy produces small tidal volumes, in contrast to conventional ventilators, which induces large pressure changes and gas volumes, and is associated with ventilator induced injury. HFOV uses alternative mechanisms of gas exchange, such as molecular diffusion. Consequently, HFOV has become the most accepted mode of ventilation support for RDS in VLBW infants, and has been shown to improve survival without an increase

8 in the incident of chronic lung disease (Moriette et al., 2001; Johnson et al., 2002; Kessel et al.,

2010).

Short Term Complications of Prematurity

It is important to quickly stabilize infants in the delivery room to reduce their risk of developing short term complications (Lemons et al., 2001). Short term complications of prematurity are defined as those occurring during the neonatal period (Eichenwald & Stark,

2008). Premature infants are increasingly susceptible to developing short term complications with decreasing birth weight and gestational age, and are the result of anatomical or functional immaturity (Faranoff et al., 2007).

Retinopathy of prematurity (ROP) is a condition occurring around 34 weeks postmenstrual age, and occurs when the retina of premature infants is incompletely vascularized.

ROP generally spontaneously resolves, but requires treatment when ROP is severe and does not resolve spontaneously (Palmer et al., 1991). Infants with ROP are more likely to have vision impairment or poor ocular outcome (Trese and Droste, 1998; Moshfeghi et al., 2004; Prenner et al., 2004; Lakhanpal et al., 2005; Repka et al., 2006).

Many VLBW infants need resuscitation at birth, most requiring endotracheal intubation and others only need resuscitation medications. Prophylactic administration of surfactant reduces the risk of respiratory complications, such as respiratory distress syndrome (RDS), pulmonary interstitial emphysema, and pneumothorax (Lemons et al., 2001). Other complications include bronchopulmonary dysplasia (BPD), and apnea of prematurity (Henderson-Smart, 1981; Frank and Sosenko, 1987). Respiratory distress syndrome (RDS) results from insufficient surfactant production prior to birth (Frank and Sosenko, 1987) and occurs about 93 percent of the time

(Stoll et al., 2010). A symptomatic patent ductus anteriosus (PDA) occurs in about 46 percent of

VLBW infants (Stoll et al., 2010). BPD is a chronic lung disease defined as dependence upon oxygen at 36 weeks postmenstrual age, occurring late in the neonatal period (Shennan et al.,

1988; Marshal et al., 1999) in approximately 42 percent of infants (Stoll et al., 2010). Apnea of prematurity occurs in about 25 percent of premature infants (Henderson-Smart, 1981).

Necrotizing enterocolitis (NEC), a gastrointestinal complication, increases the risk of neurodevelopmental disabilities (Rees et al., 2007; Schulzke et al., 2007) and growth delay later in life (Hintz et al., 2005).

Late-onset sepsis, or a positive blood culture occurring after three days of age, occurs in about 21 percent of VLBW infants (Stoll et al., 2002). Neonatal sepsis is also associated with an increase in growth impairment and poor neurodevelopmental outcomes later in life (Stoll et al.,

2004).

Short term cardiovascular complications include a patent ductus anteriosus (PDA) and systemic hypotension (Faranroff et al., 2007; Seri and Noori, 2005). PDA causes increased blood flow through pulmonary circulation and decreased blood flow through systemic circulation by shunting the blood from left to the right side of the heart (Rudolph, 1970). If a significant amount of shunting occurs, symptoms such as respiratory distress, apnea, or heart failure may present

(Thibeault et al., 1975; Cotton et al., 1978; Jacob et al., 1980; Mahony et al., 1982; Cassady et al., 1989; Schmidt et al., 2001). Systemic hypotension, occurring immediately after birth, can lead to the development of IVH (Seri and Noori, 2005; Osborn et al., 2007; Miletin and

Dampsey, 2008).

Overall, the more short term complications seen in an infant, the greater the chances that the child will experience long term complications of prematurity (Eichenwald and Stark, 2008).

Preterm Brain Complications

A child born very preterm uses different regions of the brain to process information than those regions a term infant uses. When an infant is born prematurely, the brain compensates for being underdeveloped to function properly in its new environment. These changes can have detrimental effects in long term (Jobe, 2010). The preterm infant born at 24 weeks gestational age has a brain weight around 100g with a smooth surface with no external architecture (gyri).

While at full term, an infant’s brain weighs about 350g and has a convoluted surface and great complexity (Ment et al., 2009). The brain of an ELBW neonate grows, but the surface structure is less complex than the full term brain (Ajayi-Obe et al., 2000). A preterm brain has a lower volume of deep nuclear grey matter, which can be further damaged by white matter injury (Inder et al., 2005).

New born brain injury occurs as often as 1 in 4000 live births. Greater than 95% of infants who survive a brain injury survive until adulthood, but many suffer motor and cognitive disabilities (Nelson and Lynch, 2004). Therefore, it is important to examine the brain complications of preterm infants whose susceptibility for brain injury is higher than that of term infants. Neonatal brain injury is difficult to detect in VLBW infants due to the absence of some common signs of brain injury, including lethargy, hyperexcitability, and stupor (Mercuri et al.,

2003).

Preterm infants are predisposed to brain injury due to factors including hypoxia, ischemia, hyperoxia, and maternal-fetal infection. Perinatal impacts to the brain can result in inflammation, excitotoxicity, and oxidative stress. Genetic factors cause some infants to be more

11 susceptible to these complications. These factors contribute to encephalopathy of prematurity, which is white and grey matter damage of the premature brain (Kaindl et al., 2009).

The most common brain injury in preterm infants is periventricular white-matter injury.

Periventricular white matter injury is the primary cause of chronic neurological morbidity (Deng et al., 2008). Periventricular leukomalacia (PVL), the most common type of white matter injury, is marked by microglial activation and depletion of premyelinationg oligodendrocytes (Kaindl et al., 2009). Neuropathological studies have found that diffuse white matter damage is characterized by a lack of white matter, thinning of the corpus callosum, and delayed myelination. This is caused by death of late oligodendrocyte progenitor cells (Back et al. 2001).

White-matter damage is accompanied by neuronal loss and impaired neuronal guidance.

Some preterm infant complications result from reduced connectivity between areas of the brain needed for integrating information (Kadhim et al., 2003; Kesler et al., 2006; Leviton and

Gressens, 2007; Okoshi et al., 2007).

The neonatal brain is vulnerable to oxidative damage because of its high concentrations of unsaturated fatty acids, high rates of oxygen consumption, low concentrations of antioxidants, and availability of redox-active iron (Halliwell, 1992). In the immature brain, oligodendrocyte progenitor cells are susceptible to the depletion of antioxidants and exposure to free radicals, while mature oligodendrocytes are extremely resistant to this stress (Baud et al., 2004). This vulnerability gives reason to white matter injury occurring more often in preterm infants.

Oxidative stress can lead to ischemic damage to the neonatal brain. Ischemia is a decrease in the blood supply caused by constriction or obstruction of blood vessels. This leads to tissue damage because of a lack of oxygen and nutrients (Kanold et al., 2003).

Excitotoxicity is also a factor in ischemic damage to the preterm brain. Excitotoxicity is the excessive activation of glutamanergic neurotransmitters leading to cell death (Olney, 2003).

This cell death in the neonate brain may be triggered by the impairment of the uptake of glutamate by glia causing overactive receptors (McDonald and Johnston 1990). The expressions of these glutamate receptors dictate the reaction of a newborn to brain injury. Blocking these receptors protects against hypoxic-ischemic injury to the white matter (Deng et al., 2004).

Maternal infection is another factor associated with white matter disease in the premature brain. Chorioamnionitis, inflammation of the amnion and chorion due to bacterial infection, is a risk factor for preterm infants (Wu et al., 2003). The problem with this association is that it is difficult to define chorioamnionitis, as it is rare to document it by histological examination of the placenta. This condition can be as vague as maternal fever (Khong et al., 2000).

Neonatal strokes often originate arterialy, and are caused by ischemic damage, but about

30 percent are caused by sinovenous thrombosis (deVeber et al., 2001; Wu et al., 2004). Risk factors of neonates with stroke due to cerebral venous thrombosis include coagulation abnormalities, certain genetic mutations and polymorphisms (Mercuri et al., 2001). The risk of reoccurring neonatal stroke is low at 5 percent, and is associated with complications of systemic disorders (Kurnik et al., 2003).

Intraventricular Hemorrhage

A decline in the incidence of intraventricular hemorrhage (IVH) has been seen since the

1980s where IVH occurred 50 to 80 percent of the time. It now occurs at the rate of 10 to 15 percent. The increased survival of extremely premature infants ensures that IVH remains a

13 significant problem in infants. Intraventricular hemorrhage, in premature infants, is a leading cause of brain injury (Volpe, 2001).

Intraventricular hemorrhage, as its name implies, is bleeding in or around the ventricles of the brain, which function to store cerebral spinal fluid. There are four grades of IVH. In Grade

1 IVH bleeding occurs on the edge of the ventricles but does not extend into the ventricles. In

IVH Grade 2 bleeding has progressed into the ventricles. In Grade 3 IVH the ventricles have become enlarged due to the bleed. Grade 4 IVH, the most severe, is present when bleeding is so severe that blood is forced into the tissue surrounding ventricles. IVH Grades 1 and 2 typically do not result in further complications. IVH Grades 3 and 4 (severe IVH) are less common, and can result in permanent damage to the brain (Lucile Packard Children's Hospital at Standford,

2011). Infants with severe IVH face a mortality rate near 20 percent, with more than 50 percent developing progressive ventricular dilation (Volpe, 2001).

IVH most commonly occurs in infants less than 1500 g or less than 32 weeks gestation.

Ninety percent of IVH occurs within the first three days of life (Volpe, 2001). IVH is rarely isolated, and is often accompanied by periventricular leukomalacia (PVL) (Armstrong et al.,

1987) a contributing factor of IVH (Guzetta et al., 1986). Other contributing factors include periventricular hemorrhagic infarction, and parenchymal injury (Guzetta et al., 1986).

IVH typically occurs in the frail germinal matrix (Fanaroff et al., 2007; Stoll et al., 2010).

The germinal matrix is the richly vascularized and highly cellular layer of the subependymal subventricular zone, region of the brain that gives rise to glia and neurons during infant development (Sidman et al., 1982). Infants are predisposed to hemorrhage if the structural support of the germinal matrix is insufficient (Grunnet, 1989). Astrocytic support of blood

14 vessels in the germinal matrix at 27 weeks gestation is minimal, and at 31 weeks is much more prominent (Gould and Howard, 1987).

The best method for preventing IVH would be to prevent a premature birth, but antenatal corticosteroid administration significantly reduces the risk of the IVH when premature birth cannot be prevented (Crowley, 2000). Some common preventative measures include maintaining hemodynamic stability, efforts to prevent conditions that disrupt cerebral autoregulation, and appropriate and timely resuscitation (Jim et al., 2005). Clamping the umbilical cord after thirty seconds following birth is also associated with a decrease in the incidence of IVH (Rabe et al.,

2004; Mercer et al., 2006).

Risk factors for IVH include prolonged resuscitation, respiratory distress syndrome (Palta et al., 2008), pneumothorax, seizures, and necrotizing enterocolitis (Goddard-Finegold et al.,

1997; Jen et al., 2006). Additionally, infants younger than 33 weeks gestation, whose mother had chorioamnionitis show an increased risk of developing severe IVH (Soriasham et al., 2009).

Infants born prematurely are less able to regulate cerebral blood flow which results in a pressure passive circulation in which a rise in systemic blood pressure results in an increase in cerebral blood flow, damaging the delicate germinal matrix (Papile et al., 1978; Perlman et al.,

1981; Wallin et al., 1990). As infants mature, the range of blood pressures over which they are able to autoregulate increases (Papile et al., 1985). Autoregulation can be impaired due to asphyxia (Pryds et al., 1990), hypoxia, hypocarbia, hyperoxia, and hypercarbia (Jim et al., 2005).

Activities such as movement, feeding, and crying, medical interventions such as suctioning and endotracheal intubation as well as pathologic states including seizures (Goddard-

Finegold et al., 1997; Volpe, 2001) and pneumothorax can all induce hypertension (Goddard-

Finegold et al., 1997) resulting in an increased chance of developing IVH. Premature infants

15 who have spontaneous motor activity or undergo intensive care procedures resulting in an increase in their systemic blood pressure are more likely to develop IVH.

It is uncommon for severe IVH to occur in term infants, occurring in them most frequently with the rupture of a vascular malformation (Heafner et al., 1985), alloimmune thrombocytopenia (Mao et al., 1999), sinvenous thrombosis (Wu et al., 2003), trauma, such as abdominal compression (Wehberg et al., 1992), and a diagnosis of hemophilia (Tarantino et al.,

2007).

IVH presentation can be catastrophic, saltatory, or (in 25-50 percent of cases) clinically silent. Catastrophic presentation of IVH is the least common, and is characterized by inappropriate antidiuretic hormone (ADH) secretion, bradycardia, hypotension, falling hematocrit levels, and a bulging anterior fontanel. Other signs of catastrophic IVH include cranial nerve abnormalities, such as the pupils being fixed to light, generalized tonic seizures, decerebrate posturing, flaccid weakness, irregular respirations such as, apnea or hypoventilation, and coma or stupor. In a saltatory presentation of IVH, respiratory function is sometimes affected as well as the presence of hypotonia, an altered level of consciousness, and a decrease in subtle, spontaneous, or elicited eye movements. Saltatory presentation of IVH typically occurs within hours to several days (Tarby and Volpe, 1982).

Diagnosis of IVH is most commonly done via cranial ultrasound. Cranial ultrasounds of

IVH Grades 1, 2, 3 are shown in Figures 1, 2, 3 and 4, respectively below. Cranial ultrasound screening for IVH is routinely performed on premature infants because nearly half of all incidences of IVH are clinically silent (Ment et al., 2002). Another diagnostic measure used to detect IVH is a lumbar puncture. With a lumbar puncture, the cerebral spinal fluid (CSF) of an

16 individual with IVH would contain high protein concentrations and red blood cells (Volpe,

2001).

Figure 1: Cranial ultrasound of Grade 1 IVH (coronal view). The ultrasound shows bleeding in the germinal matrix but does not extend into the ventricles. (© Auckland. http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/HUSS/Images/IVH/Grade1/Grade %201%20coronal.jpg)

Figure 2: Cranial ultrasound of Grade 2 IVH (coronal view). The ultrasound shows bleeding extending into the ventricles, but does not result in extension of the ventricles. (© Auckland http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/HUSS/Images/IVH/Grade2/Grade 2Coronal2.jpg)

Figure 3: Cranial ultrasound of Grade 3 IVH (coronal view). The ultrasound shows a bilateral bleed causing extension of the ventricles. (© Auckland http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/HUSS/Images/IVH/Grade3/Day% 202b.jpg)

Figure 4: Cranial ultrasound of Grade 4 IVH (coronal view). The ultrasound shows a bilateral bleed extending past the ventricles into the brain tissue. (© Auckland http://www.adhb.govt.nz/newborn/TeachingResources/Radiology/HUSS/Images/IVH/Grade3/Day% 204a.jpg)

Supportive treatment to limit the damage of IVH includes aiming to minimize further complications, as well as preserving cerebral perfusion. Treatment can include providing nutritional, fluid and metabolic support, as well as maintaining systemic blood pressure to prevent hypertension or hypotension, and the use of supportive oxygenation and ventilation techniques (Volpe, 2001).

The severity of the long term outcomes increases with the severity of IVH as well as decreasing gestational age and birth weights (Sherlock et al., 2005). Some of the long term complications of IVH include cognitive dysfunction, cerebral palsy, major neurosensory disabilities (Sherlock et al., 2005), and intellectual disability (formerly reported as mental retardation) (Luu et al., 2009). Other complications include posthemorrhagic hydrocephalus, and major cognitive impairments, as well as other developmental disabilities (Pinto-Martin et al.,

1999; Murphy et al., 2002). Many children with these complications require special education services in school (Vhor et al., 2003). Adverse neurodevelopmental outcomes are greatest among those ELBW infants having severe IVH (Adams-Chapman et al., 2008; Brouwer et al., 2008).

Long Term Complications of Prematurity

Premature children generally have a lower body mass index, are shorter, lighter, and have a smaller head circumference than those born full-term due to reduced growth (Bracewell et al.,

2008). Children born preterm have increased prevalence of chronic medical conditions such as gastroesophageal reflux (Omari et al., 1998), bronchopulmonary dysplasia (Jobe & Bancalari,

2001), as well as having an increased risk of hearing (Thompson et al., 2001) and vision impairments (Knight-Nanan & O'Keefe, 1996; Hebbandi et al., 1997; Repka et al., 1998; Quin et al., 1998; Holmstrom et al., 1999) and sudden infant death syndrome (Verma & Sridhar, 2003).

Premature infants are more likely to be rehospitalized for recurrent illnesses including feeding problems (Korvenranta et al., 2009), surgical issues (Harper et al., 1975; Peevy et al.,

1986; Powell et al., 1986; Rajput et al., 1992; McCourt & Griffin, 2000), infections, notably respiratory syncytial virus infection (Nachman et al., 1997; McCormick & Tubman, 2002), and respiratory problems including asthma compared to infants born full-term (Koivisto, 2005;

Underwood et al., 2007). Premature children also have an increased risk of having impaired lung function, which may result in an increase in respiratory symptoms, and a reduced exercise and lung capacity (Smith et al., 2008).

In ELBW children, neurodevelopmental complications result in more functional limitations such as developmental, growth and motor delay, as well as decreased social skills, limited physical ability, and sensorineural deficits. Children born ELBW are also more likely to require equipment or help for activities of daily life such as washing, dressing and feeding, as well as increased medication use. In addition, ELBW children are at increased risk of requiring additional services such as educational programs individualized to their needs, other special school arrangements, and acute care visits to specialized health care professionals than children born at a normal birth weight (Stein et al., 2006).

As adults, those born prematurely seem to be more likely to have higher blood pressure and an increased resistance to insulin compared to adults born full-term (Hovi et al., 2007;

Rotteveel et al., 2008). During their late teens, ELBW adults score higher on measures of inattention, anxiety, depression, withdrawn behavior, and social problems. In addition, VLBW adults in the same age group report lower rates of alcohol and drug use, sexual activity, and pregnancy than adults born at normal birth weight (Hack et al. 2004). An association can be made between decreased reproduction in adulthood and prematurity compared to the reproductive rates of full-term adults. Additionally, women who were preterm also have a higher risk of having a preterm child. However, men born prematurely have no increased risk of their children being born prematurely (Swamy et al., 2008).

Neurodevelopmental Outcomes of Premature Infants

Common neurological impairments associated with prematurity include mental retardation (cognitive impairment), cerebral palsy (CP), blindness, and hearing impairments.

These are the highest in ELBW infants (Hack and Farnaroff, 2000). Research centers and hospitals have reported a range of occurrences of neurological impairment. The variability of this data can be contributed to rates of neonatal morbidities and differences in treatment management style (Vohr et al., 2004).

The most common neurological impairment is cognitive impairment, which is defined as a score more than two standard deviations below the mean on standardized cognitive tests

(Bayley, 1993). Rates of cognitive impairment are inversely proportional to gestational age and birth weight. While testing of cognition is done during infancy, it is not always predictive of cognitive function later in life (Jobe, 2010).

ELBW and VLBW school age children have lower Intelligence Quotient (IQ) scores and higher rates of cognitive impairment compared with their normal peers (Marlow et al., 2005).

Compared with their normal peers, VLBW and ELBW children have impairments of executive functioning, visual-motor skills, and memory. Infants born LBW are also more likely to develop learning disabilities such as attention deficit disorder or attention deficit hyperactivity disorder

(Hack et al., 2002).

Other neurological impairments of prematurity affect motor functions. The main concern here is cerebral palsy (CP). Cerebral Palsy is defined as “a disorder of movement and posture that involves abnormalities in tone, reflexes, coordination and movement, delay in motor milestone achievement, and aberration in primitive reflexes (Vohr et al., 2005).” The most common form of CP is spastic diplegi: spastic quadriplegia, and hemiplegia (Bracewell and

Marlow, 2002; Vohr et al., 2005; Stephens and Vohr, 2010). Some LBW infants develop soft neurological signs of motor impairment. Soft signs include deviations in speech, balance, coordination, gait, tone, and fine motor or visual motor tasks that do not signify localized brain dysfunction (Breslau et al., 2000). Standard evaluations of motor function include muscle tone, strength, reflexes, joint angles, and posture.

Neurosensory disabilities are not as common as cognitive and motor impairments, but are prevalent in ELBW infants. Visual impairments include unilateral or bilateral blindness, myopia, and strabismus. Hearing impairments requiring amplification occur in 1% to 9% of ELBW infants (Vohr et al., 2004). Mild hearing impairments are more common (Hack et al., 2005).

Prematurity, especially VLBW infants, has been associated with many behavioral and psychological diagnoses and disabilities. Evaluation of behavior is often obtained by parents and teachers and measures behavior, attention, adaptive skills, and depression. There is concern that low birth weight and gestational age presents a risk for autism spectrum disorders, but the true risk is unknown (Schendel and Bhasin, 2008).

Diagnostic Developmental Tests

The Bayley Scales of Infant Development - Second Edition (BSID-II) is a developmental test of both cognitive and motor skills for infants one month to 42 months (Bayley Scale, 2011).

BSID-II has three characterized scales evaluating the mental (mental scale), motor (motor scale), and behavioral development (behavioral scale) of a child (BSID-II, 2011). The mental scale gives a normalized Mental Developmental Index (MDI) and Psychomotor Development Index

(PDI) standard score (BSID-II, 2011). The motor scale tests large muscle coordination, degree of body control, fine manipulatory skills involving he fingers and hands as well as stereognosis,

22 dynamic movement, dynamic praxis, and postural imitation (BSID-II, 2011). The behavioral scale is an assessment of the child's ability to perform the mental and motor tests looking at motor quality, orientation/engagement, attention/arousal, as well as emotional regulation and is used as a supplementary scale to the mental and motor scales (BSID-II, 2011).

The BSID-II was normalized to a sample of 1,700 children randomly selected infants between the ages of one month to 42 months (BSID-II, 2011). The manual for the BSID-II provides information about specific groups as reference, including children who have the HIV antibody, Down's syndrome, are developmentally delayed, are autistic, have frequent ottis media, were asphyxiated at birth, who were prenatally exposed to drugs, or were born prematurely

(BSID-II, 2011).

The Bayley Scales of Infant and Toddler Development --Third Edition (Bayley-III) also tests children from one month to 42 months of age (Bayley-III, 2011). The Bayley-III is similar to the BSID-II in the fact that they are both testing the same basic aspects of development; however the Bayley-III is a bit more comprehensive. The Bayley-III has five scales corresponding to the five developmental domains in which the children are evaluated: social- emotional, adaptive behavior, cognitive, motor, and language development (Bayley-III, 2011).

The Bayley-III focuses on the developmental skills the child possesses, but also has scores children with a scaled and composite score in the fields of cognition, motor (fine and gross motor), and language (both receptive and expressive language) (Bayley, 2006).

The social-emotional domain of the Bayley-III is meant to monitor emotional and social functioning, the progress of early intervention, as well as determining if the child has mastered the early aspects of their social-emotional growth, age related milestones and detecting developmental social-emotional problems or deficits (Bayley-III, 2011).

The adaptive behavior domain of the Bayley-III includes self-care, self-direction, health and safety, home living, leisure, functional pre-academics, social, motor, communication, and community use (Bayley-III, 2011).

The cognitive domain of the Bayley-III includes exploration and manipulation, habituation, memory, concept formation, object relatedness, sensorimotor development, visual preference, visual acuity, as well as object permanence and other cognitive processing abilities, as well as age-appropriate cognitive skills (Bayley-III, 2011). The motor domain of the Bayley-

III includes gross motor and fine motor skills on which the children are evaluated (Bayley-III,

2011). The language domain of the Bayley-III is comprised of two communication groups: expressive communication and receptive communication (Bayley-III, 2011).

The manual for the Bayley-III includes reference material on children who are premature, small for gestational age, at-risk, have Down's syndrome, pervasive developmental disorder, cerebral palsy, language impairment, and FAS/polysubstance use (Bayley-III, 2011). The scores generated by the Bayley-III include information on percentiles, age equivalents, T score, and cut scores (Bayley-III, 2011).

PROJECT PURPOSE

The purpose of this project was to bridge the information disconnection between the neonatal intensive care unit (NICU) at the UMass Memorial Medical Center (where IVH is first likely to be diagnosed) and their Developmental and Behavioral Pediatric Follow-Up clinic

(where subsequent developmental outcomes are first identified). Physicians from the NICU at

UMass Memorial Medical Center require information for parents facing the decision as to whether to continue life sustaining care premature infant when he/she has a particular neonatal complication. Standardized health and developmental follow-up forms are needed for physicians in the NICU to attain follow-up data on children who suffered from similar conditions in the

NICU. With this information parents can understand what complications their premature infant my face later in life and will be better able to make an informed decision on whether to continue to provide life-sustaining care to their infants with severe IVH who may be neurologically devastated. In this project, an analysis of infants with severe IVH born under 1000g was performed to demonstrate potential correlations with neurodevelopmental follow-up statistics.

Physicians can use this information to show parents the neurodevelopmental outcomes of severe

IVH infants at UMass and the chances of their Infant with IVH developing neurological impairments.

METHODS

Pediatric Follow-Up Form Development

Standardized Follow-up Health Status and Developmental Status forms were created for use by the UMass Pediatric Developmental and Behavioral Follow-up Clinic and neonatal intensive care unit (NICU) to track the development of children after discharge from the NICU.

These forms were based on the Vermont Oxford Network (VON) Forms (Appendicies 1a & b) and altered to fit the needs of UMass Memorial Medical Center (UMMC). VON evaluates infants between 18 and 24 months but the follow-up clinic sees children of all ages, thus there is a wider range of information to collect.

Dr. Robin Adair of the UMass follow-up clinic and Dr. Alan Picarillo of the UMass

NICU were interviewed to identify what information needed to be captured during follow-up visits. These discussions provided insight on which data the follow-up clinic captures for children at different ages, and what information is necessary for neurodevelopmental diagnosis.

Developmental and Behavioral Pediatric Follow-up appointments were observed to better understand the process of diagnosis.

The UMMC Follow-up Health Status and Developmental Status forms were designed for a relatively new database system at the follow-up clinic, AllScripts. The forms were designed with Microsoft Word, and numerically coded for electronic entry. A total of seven forms were developed and are listed in Table 1.

Table 1: UMass follow-up Clinic Forms

Age Range Form (Months . Days)

Developmental Status 0.0 – 15.29 Developmental Status 16.0 – 26.0 Developmental Status 26.1 – 42.0 Developmental Status >42.1 Health Status 0.0 – 15.29 Health Status 16.0 – 26.0 Health Status >26.1

Severe IVH Database Setup

Infants born under 1000g with severe IVH (grades 3 and 4) were studied to determine trends in neurodevelopment. An Excel database was set up including all infants with severe IVH, born under 1000 grams, at the UMMC NICU from 2003 to 2009 (n = 17). Because past information was not recorded on the newly developed follow-up forms, data was extracted from paper files and was recorded in the excel database. Independent variables included all perinatal conditions. Dependent variables were all neurodevelopmental follow-up conditions.

Neurodevelopment conditions were determined by the physicians at the UMMC Pediatric

Follow-up Clinic. A list of the independent and dependent variables used in data analysis are provided in Table 2.

Table 2: Severe IVH Independent and Dependent Variables

Independent Variables Dependent variables (Perinatal Conditions) (Neurodevelopmental)

Grade of IVH Early Intervention Mode of Delivery Cerebral Palsy (CP) Antenatal Steroids Rehospitalization Bayley II MDI scores Bayley III scores Prescription Glasses Hearing Impairment

A comprehensive list of variables collected can be found in Appendix 2.

Data Analysis

The data collected in the severe IVH database (n=17) was compared to infants born at

UMMC between 2003 and 2009 that were under 1000g but did not have severe IVH (n = 179) and infants born between 2003 and 2007, under 1000g in the VON data base (n = 85175). A two tailed Fisher’s Exact Test, (Quick Calcs, 2005), was used to compare the occurrence of the neurodevelopmental outcomes in the different populations. The two tailed Fisher’s Exact Tests are listed in Table 3.

Table 3: Two Tailed Fisher’s Exact Tests

1. Cerebral Palsy: Severe IVH Infants vs. No Severe IVH Infants (UMass) 2. Severe Cognitive Impairment vs. No Severe Cognitive Impairment: Severe IVH Infants vs. No Severe IVH Infants (UMass) 3. Moderate Cognitive Impairment vs. No Cognitive Impairment: Severe IVH Infants vs. No Severe IVH Infants (UMass) 4. Eyeglasses: Severe IVH Infants vs. No Severe IVH Infants (UMass) 5. Hearing Impairment: Severe IVH Infants vs. No Severe IVH Infants (UMass) 6. Rehospitalization: Severe IVH Infants vs. No Severe IVH Infants (UMass) 7. Grade of Severe IVH (3 or 4): Use of Antenatal Steroids 8. Grade of Severe IVH (3 or 4): Mode of Delivers (Vaginal Delivery or Cesarean Section)

The occurrence of severe IVH and cerebral palsy in infants born under 1000g at UMMC and in VON was compared. The occurrence of severe IVH was compared to see how UMMC compares to the average NICU that submits data to VON. The occurrence of cerebral palsy was used as a positive control in which to compare UMMC and VON. A Two Tailed Fisher’s Exact

Test could not be used for these comparisons because of the large number of infants, so a Chi

Squared Analysis with a Yates Correction was used for these comparisons.

The cognition levels of these children were determined by examining their Bayley II and

III test scores completed between ages 14 and 26 months. Some children were given either the

Bayley II or III. If both test were administered the Bayley III was used for analysis. The Bayley

II has one index score for cognition termed the Mental Development Index (MDI) score. Scores of 85 or above are considered normal, scores 70 to 84 are considered moderately impaired and scores below 70 are considered severely impaired. The Bayley III test produces multiple scores so as advised by Dr. Robin Adair and Dr. Alan Picarillo, the Cognitive Index scores and

Language Index scores were averaged to determine an equivalent MDI score. The average of these scores was used to determine the degree of cognitive impairment. Again, scores of 85 or above are considered normal, 70 to 84 are considered moderately impaired and scores below 70 are considered severely impaired. All other neurodevelopmental outcomes were found directly in the patients’ paper charts.

The Fisher’s Exact Test was used to compare the occurrence of neurodevelopmental outcomes in different infant populations, calculate the probability that a difference in two categories is a significant difference or a coincidence (not significant). The Fisher’s Exact Test calculated P values for each comparison. The P value is the probability that a difference will be observed that is as large as or larger than observed if the null hypothesis were true. The Null hypothesis for each of these comparisons was that there is no difference between the groups. A

P value of 0.05 or less is considered to suggest a significant difference between two groups.

Meaning there is only a 5% chance that the difference is insignificant.

RESULTS

This project helped bridge the information disconnection between the neonatal intensive care unit (NICU) at the UMass Memorial Medical Center (UMMC) and their Developmental and

Behavioral Pediatric Follow-UP Clinic. Physicians from the NICU will now be able to more efficiently acquire information from the Follow-Up Clinic from the developed Health and

Developmental Status Forms, which will be used in the AllScripts database. The new Health and

Developmental Status Forms can be found in Appendices 3a-g. This information will enable parents to understand what complications their premature infant may face later in life.

An analysis if infants with severe intraventricular hemorrhage (IVH) under 1000g was conducted to demonstrate the advantages of the Health and Developmental Status Forms in the attainment of neurodevelopmental follow-up statistics. The results show that severe IVH in premature infants born under 1000g correlates with certain neurodevelopmental complications.

All but one of the severe IVH infants received Early Intervention to assist in their neurodevelopment.

A positive control was performed to ensure that UMass and the Vermont Oxford

Network (VON) had accurate follow up data. As a positive control, the occurrence of cerebral palsy (CP) in ELBW infants, from 2003 to 2007, was compared between UMMC and VON. The occurrence of CP was used because it is a possible neurodevelopmental outcome of any ELBW infant. A Two-tailed Fisher’s Exact Test indicated no difference in the occurrences of CP in either population. Because there is no significant difference between the two populations, the positive control indicates that these two populations are comparable, and therefore the results of

30 the statistical analysis between the groups are reliable. A Graph of the Occurrence of CP in

ELBW infants at both UMass and Von is displayed in Figure 5.

Occurence of Cerebral Palsy UMMC vs. VON

50% Network 45% 40%

35% 30% 25% Cerebral 20% Palsy

Occurrence(%) 15% 10% 8.0% 4.5% 5% 0% UMMC VON Network

Figure 5: Occurrence of Cerebral Palsy in ELBW Infants: UMass vs. VON. The occurrence of cerebral palsy at UMass compared to the VON Network. This functions as a positive control showing no statistical difference in the overall occurrence of cerebral palsy at UMass (n=187) compared to the VON Network (n=4007) with a P value of 0.0692.

To determine how well UMMC is stabilizing ELBW infants and preventing severe IVH,

The occurrence of severe IVH in ELBW infants, between 2003 and 2007, was compared between UMMC and VON using a Chi Squared analysis with Yates correction. The analysis showed that the occurrence of severe IVH in ELBW infants at UMass was statistically significantly lower than infants reported to the national Vermont Oxford Network database. A

Graph of the occurrence of severe IVH at UMass and VON is displayed in Figure 6.

Occurence of Severe IVH UMMC vs. VON 50% 45% 40% 35% 30% *** 25% Occurrence of IVH 20% 17%

Occurrence(%) 15% 10% 7.8% 5% 0% UMMC VON Network

Figure 6: Occurrence of Severe IVH: UMass vs. Von. The occurrence of severe IVH in preterm infants at UMass (n=218) was compared to the occurrence in preterm infants in the Vermont Oxford Network (n=85175). The occurrence of IVH was extremely statistically significantly lower (***) at UMass than in the Vermont Oxford Network with a P value of 0.0004.

One possible neurodevelopmental complication is cerebral palsy. To determine if severe

IVH correlates with cerebral palsy, a Two-tailed Fisher’s Exact Test was performed for ELBW infants from the UMMC NICU with and without severe IVH, from 2003 to 2009. ELBW infants with severe IVH were 22% more likely to develop cerebral palsy than ELBW infants without

IVH. A Graph of the Occurrence of Cerebral Palsy in Infants with Severe IVH and Infants without severe IVH is displayed in Figure 7.

Occurence Cerebral Palsy Severe IVH vs. No Severe IVH 50% 45% 40%

35% ** 30% 24% 25% Cerebral Palsy 20%

Occurrence(%) 15% 10% 5% 2% 0% Severe IVH No Severe IVH

Figure 7: Occurrence of Cerebral Palsy: Severe IVH vs. No Severe IVH. The occurrence of cerebral palsy in preterm infants with severe IVH (n=17) was s found to be very statistically significantly higher (**) in the severe IVH infants than in the no severe IVH infants with a P value of 0.0032.

Another possible neurodevelopmental complication is cognitive impairment. To determine if severe IVH correlates with moderate or severe cognitive impairment a Two-tailed

Fisher’s Exact Test was performed for ELBW infants from the UMMC NICU with and without severe IVH, from 2003 to 2009. ELBW infants with severe IVH were 38% more likely to become moderately cognitively impaired than ELBW infants without IVH. Severe IVH infants are no more likely to develop severe cognitive impairment than infants without severe IVH. A

Graph of the Occurrence of cognitive impairment in Infants with Severe IVH and Infants without severe IVH is displayed in Figure 8.

Cognitive Impairment Severe IVH vs. No Severe IVH (2003-2009) 100% **

80% 75%

58% 60% 42% Severe IVH 40% No Severe IVH Occurence(%) 20% 20% 5% 0% 0% Normal Cognition Moderate Cognitive Severe Cognitive Impairment Impairment

Figure 8: Cognitive Impairment: Severe IVH vs. No Severe IVH. The Cognition of preterm infants with severe IVH (n=17) was compared with the cognition of preterm infants without severe IVH (n=158). All Cognition tests were performed between 14 and 26 months corrected age. There was no statistical significant difference in the occurrence of severe cognitive impairment in either the severe IVH group or the no severe IVH group with a P value of 1. The infants with severe IVH had a very statistically significantly (**) higher occurrence of moderate cognitive impairment than infant without IVH with a P value of 0.0036.

To determine if there is a correlation between sensory impairment, particularly sight and vision, a Two-tailed Fisher’s Exact Test was run to compare the need for eyeglasses and any hearing impairment in ELBW infants with and without severe IVH between 2003 and 2009.

These sensory impairments were found to correlate with severe IVH. ELBW infants with severe

IVH were 30% more likely to need eyeglasses than infants without severe IVH. ELBW infants with severe IVH were also 13% more likely to have a hearing impairment. A graph of the occurrence of sensory impairments in infants with and without severe IVH is displayed in

Figure-9.

Sensory Impairment Severe IVH vs. No Severe IVH 50% 45% ** 40% 36% 35% 30% 25% * Severe IVH 20% 14% No Severe IVH

Occurrence(%) 15% 10% 6% 5% 1% 0% Eyeglasses Hearing Impairment

Figure 9: Sensory Impairment: Severe IVH vs. No Severe IVH. The occurrence of sensory impairments, the need for eyeglasses and any hearing impairment, in premature infants with severe IVH (n=17) was compared to the occurrence in infants without severe IVH (n=165). Premature infants with severe IVH had a very statistically significantly (**) higher occurrence of the need for eyeglasses with a P value of 0.0027. Severe IVH Infants also had a statistically significantly (*) higher occurrence of hearing impairment than did infants without severe IVH.

The occurrence of rehospitalization of ELBW infants with and without severe IVH, between 2003 and 2009, was compared using a Two-tailed Fisher’s Exact Test. There was no significant difference between the rehospitalization of infants with and without severe IVH. No correlation between severe IVH and rehospitalization was found. A graph of the occurrence of rehospitalization is displayed as Figure 10.

Occurrence of Rehospitalization No Severe IVH vs. Severe IVH 100% 90% 80% 64.7% 70% 60% 50% 42.0% 40% Rehospitalization Occurence(%) 30% 20% 10% 0% No Severe IVH Severe IVH

Figure 10: Occurrence of Rehospitalization: No Severe IVH vs. Severe IVH. The occurrence of rehospitalization after discharge from the NICU of preterm infants with severe IVH (n=17) was compared to its occurrence for preterm infants without IVH (n=162). The Occurrence of rehospitalization was found not to be statistically different in the severe IVH infants than in the no severe IVH infants with a P value of 0.1213.

To determine whether mode of delivery, either vaginal delivery or cesarian section, correlates with the grade of severe IVH, a Two-tailed Fisher’s Exact Test was performed. There was no significant difference between the grade of IVH with vaginal delivery or cesarian section.

Thus, no correlation was found between mode of delivery and severity of IVH. A graph of this comparison can be found in Figure 11.

Grade of Severe IVH Vagenal Delivery vs. Cesarian Section 100

60% 58% 60 42% 40% IVH Grade 3

40 IVH Grade 4 Occurrence(%) 20

0 Vaginal Delivery C-Section

Figure 11: Severity of IVH Compared to Mode of Delivery. The severity of IVH, grade 3 (n=8) or grade 4 (n=9), was compared to the mode of delivery, vaginal or cesarian section. No statistically significant difference in grade of severe IVH was found based on the mode of delivery, with a P value of 0.6199.

The severity of IVH was compared to the administration of antenatal steroids with a

Two-tailed Fisher’s Exact Test. No significant difference in severity of IVH was found with or without the use of antenatal steroids. These results can be seen in Figure 12.

Grade of Severe IVH Antenatal Steroids vs. No Antenatal Steroids 100

80 67% 60 55% 45% IVH Grade 3

40 33% IVH Grade 4 Occurrence(%) 20

0 No Antenatal Steroids Antenatal Steroids

Figure 12: Severity of IVH Compared to Use of Antenatal Steroids. The severity of IVH, grade 3 (n=8) or grade 4 (n=9), was compared to the use of antenatal steroids. No statistically significant difference in grade of severe IVH was found based on the use of antenatal steroids, with a P value of 0.6199.

Severe IVH was found to have correlations with cerebral palsy, moderate cognitive impairments, as well as impairments but not with rehospitalization or severe cognitive impairments at UMMC. No correlation was found between the severity of IVH and the mode of delivery or use of antenatal steroids at UMMC. This information can be used to inform parents and aid in the difficult decision of resuscitation and continuation of medical care for their ELBW infant.

DISCUSSION

To compare different variables recorded in this severe IVH study, two statistical analytic tests were performed, including two-tailed Fisher’s exact test and Chi Squared analysis with

Yates correction. A Chi Squared analysis with Yates correction shows that there are significantly fewer cases of severe IVH at UMass Memorial Medical Center (UMMC) compared with the

VON Network as a whole. This data suggests that the NICU at UMMC is doing a better job stabilizing babies born <1000g than the average VON Network center. The chi squared analysis with Yates correction was performed for this comparison because the Fisher’s exact analysis could not be performed because of the large population size. Fisher’s exact tests were used for all other statistical analyses. Statistical analysis shows a very strong correlation between babies with severe IVH and the development of moderate cognitive impairment later in life. However, no correlation was found with severe cognitive impairment. At UMMC, there is a very strong correlation between babies who had severe IVH and the development of cerebral palsy as an infant. In addition, a very strong correlation was found between babies who had severe IVH needing eyeglasses later in life due to visual impairments. A strong correlation was found between babies, at UMMC, who had severe IVH and the occurrence of hearing impairment.

These correlations indicate that severe IVH increases the risk of poor neurodevelopmental, motor and sensory outcomes.

According to the Fischer’s exact test there is no statistical significance between the incidence of CP at UMMC compared to the VON network, which acts as a positive control, showing that UMass Memorial Medical Center is comparable to the VON Network. There was also no significant difference in rehospitalization in children who had severe IVH compared to

39 those who did not have severe IVH at UMMC. This indicates that infants at UMMC with severe

IVH are not at an increase risk of rehospitalization compared to those who did not have severe

IVH. Other analyses showing no statistical significance were the administration of antenatal steroids compared to the grade of severe IVH (grade 3 vs. grade 4), the mode of delivery compared to the grade of severe IVH, and the occurrence of cerebral palsy compared to the grade of severe IVH. These comparisons likely did not show statistical significance due to small sample sizes (Grade 3 IVH, n=8; Grade 4 IVH, n=9). If the populations were larger, likely there would be a greater chance of these differences being significant.

Had the sample sizes been larger for the comparisons of the grade of severe IVH and mode of delivery or antenatal steroid use a correlation would likely have been found since these correlations have been found with larger populations. The lack of a correlation between severe

IVH and increased incidence of rehospitalization is also interesting because the expectation would be that a correlation would exist between the two, based on previous research. This begs the question of whether trends found from analyzing single hospitals with a small population size of interest are reliable. If data is pooled over 30 years in order to get a large enough populations, size the results of analysis will likely be unreliable due to advances in patient care during those

30 years. It would be most beneficial to pool data from multiple hospitals for analyzing trends in order to have a large enough sample size to obtain reliable correlations over a shorter time period.

The forms created for UMass will allow physicians in the NICU to find these types of correlations for babies with various NICU complications born at UMMC. This would allow physicians in the NICU to give parents more accurate information regarding the possible sensory, motor, neurodevelopmental or other outcomes their child faces in order to make a better

40 educated decision about whether to continue to provide life-sustaining care to their infants who may be neurologically devastated.

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APPENDIX

Appendix 1a: VON Developmental Status Report

Appendix 1b: VON Health Status Report

Appendix 2: Comprehensive List of Variables

Independent Variables Gestational age (GA) (criteria: days from LMP (last menstrual period) documented by OB, or ultrasound dating

Birth weight

Weight for gestational age 3. Large for gestational age (LGA) 1. Small for gestational age (SGA) 2. Average for gestational age (AGA) Apgar, 5 minute AP5 1. Not applicable (N/A) 1-10 2. Score 9. Unknown Mode of delivery VAGDEL 1. C-section (CS) 0. No (C-section) 2. Vaginal 1. Yes 9. Unknown

Chronic Lung Disease Ox36 1. Yes 0. No 0. No 1. Yes 7. Not applicable 7. Not applicable 9. Unknown 9. Unknown

Intraventricular Hemorrhage (IVH) UGRADE (highest grade, unilateral or bilateral) 0-4 1. Grade 3 7. Not applicable 2. Grade 4 9. Unknown Periventricular Leukomalacia 1. None PVL 2. Cystic 0. No 1. Yes (Cystic) 3. Diffuse 7. Not applicable 9. Unknown

Retinopathy of prematurity (ROP) 1. None 2. < Grade 2+ 3. Grade 2+ (plus disease) 4. Grade 3

5. Grade 4 ISTAGE 0-4 7. Not applicable 9. Unknown

Retinopathy of prematurity (ROP) laser ROPSURG treatment 0. No 1. Not applicable (N/A) 1. Yes 2. Yes 7. Not applicable 3. No 9. Unknow Hearing (BAER) 1. Pass bilaterally 2. Referred one ear 3. Referred both ears 4. Not recorded

Sepsis SEPSIS 1. None 0. No 2. Symptoms & blood culture (cx) positive 1. Yes 3. Symptoms and urine culture (cx) 9. Unknown positive 4. Symptoms and cerebral spinal fluid (csf) culture (cx) positive

Antenatal steroids ASTER 1. None 0. No 2. Betamethasone (BMZ) or Celestone 1. Yes 3. Other (please note) 9. Unknown Antenatal Steroid Doses 1. Not eligible (criteria: 23-5/7 to 34-0/7 wks gest) 2. None 3. 1 dose 4. 2 doses 5. Not known Chorioamnionitis evidence (maternal CHORIO fever, other mention) 0. No 1. Yes 1. Yes 2. No 9. Unknown

Dependent Variables Cerebral palsy (CP) Cpalsy CPImp 1. Yes 1. Yes 1. Diplegia 2. No 0. No 2. Hemiplegia 3. Paraplegia

Seizures/Epilepsy SeizAdm 1. Yes 1. Yes 2. No 0. No SEIZURE 0. No 1. Yes 7. Not applicable 9. Unknown

Hearing impaired HearImp HearingTest 1. Yes 0. Not impaired 0. No 2. No 1. One ear 1. Yes 2. Both ears 9. Unsure

Vision impaired Blindness 1. Yes 0. Not blind 2. No 1. One eye 2. Both eyes 9. Unsure Hospitalizations since NICU discharge 1. 0 2. 1 3. 2 4. 3 5. 4+ Surgery since NICU discharge Surgery 1. 0 0. No 2. 1 1. Yes 3. 2 9. Unknown 4. 3 5. 4+

Bayley Scales of MDI MDIIndex Infant 0. No Development II: 1. Yes MDI 1. Not applicable (N/A) 2. MDI score

MDIRaw Bayley Scales of PDI PDIIndex PDIRaw Infant 0. No Development II: 1. Yes PDI 1. Not applicable (N/A) 2. PDI score

Bayley Scales of CogComp CogCompIndex CogCompRaw Infant and 0. No Toddler 1. Yes Development III: Cognitive 1. Not applicable (N/A) 2. Composite score

Bayley Scales of LangComp LangCompIndex LangCompRaw Infant and 0. No Toddler 1. Yes Development III: Language 1. Not applicable (N/A) 2. Composite score

Bayley Scales of MotorComp MotorCompIndex MotorCompRaw Infant and 0. No Toddler 1. Yes Development III: Motor 1. Not applicable (N/A) 2. Composite score

Appendix 3a: UMass Memorial Medical Center Developmental Status Report (0 to 15-29/30 months)

Date Last Seen ___/___/_____ (MM/DD/YYYY)

SECTION A: GROWTH PARAMETERS Corrected Age Growth Parameters Were Obtained

(months/days): __ __ months __ __ days Weight: __ __ . __ __ kg Head __ __ . __ __ cm Circumference: Length: __ __ . __ __ cm or __ __ . __ __ in Early Intervention Received: □ Yes □ No

SECTION B: VISION AND HEARING Formal Ophthalmologic Exam: □ Yes □ No Blindness: □ One eye □ Both eyes □ Not blind □ Unsure Prescription Glasses: □ Yes □ No Formal Hearing Test: □ Yes □ No Hearing Impairment: □ One ear □ Both ears □ Not deaf □ Unsure Amplification: □ Yes □ No

SECTION C: CEREBRAL PALSY Cerebral Palsy: □ Yes □ No If Yes, a. Impairment: □ Diplegia □ Hemiplegia □ Quadriplegia If No, b. Muscle tone: □ Hypotonia □ Hypertonia □ Both (hypo- & hypertonia) □ Normal

SECTION D: GROSS MOTOR MILESTONES Sits Independently: □ Yes □ No If No, a. Sits with support: □ Yes □ No Walks ten (10) steps independently: □ Yes □ No If No, a. Walks ten (10) steps with support: □ Yes □ No

SECTION E: DEVELOPMENTAL TESTING Bayley Scales of Infant Development: □ Completed □ Partly Completed □ Not Performed If completed or partially completed, a. Corrected age used in scoring: __ __ months __ __ days b. Results: Check all sections that apply. BSID-II □ MDI: Raw Score: ______Index Score for Corrected Age: ______BSID-II □ PDI: Raw Score: ______Index Score for Corrected Age: ______BSID-III □ Cognitive: Scaled Score: ______Composite Score: ______BSID-III Sum Scaled □ Language: Score: ______Composite Score: ______BSID-III Sum Scaled □ Motor: Score: ______Composite Score: ______

BINS: □ L □ M □ H

IF partly completed or not performed, Check why: □ Neurosensory impairment (blind or deaf) □ Too severely delayed □ Uncooperative □ Other reason: ______Other Developmental Test Performed: □ Yes □ No If Yes, Abnormal results: □ Yes □ No

SECTION F: OVERALL CLINICAL APPRAISAL Clinical Appraisal: Cognitive Function: □ Normal □ Suspect □ Impaired Language: □ Normal □ Suspect □ Impaired Motor Function: □ Normal □ Suspect □ Impaired

61 Appendix 3b: UMass Memorial Medical Center Health Status Report (0 to 15-29/30 months)

Date Last Seen ___/___/_____ (MM/DD/YYYY)

Birth Weight (g): □ <1000 □ 1000-1250 □ 1251-2000 □ 2001-2500 □ >2500 Gestational Age (weeks): □ <28 □ 28 – 38 □ 30 1/7-34 □ 34 1/7 -36 6/7 □ 37 – 42 □ >42

SECTION A: HEALTH STATUS Corrected Age at the Follow-Up Visit: __ __ months __ __ days (months/days)

SECTION B: LIVING SITUATION Maternal Age at Infant Birth: __ __ Years □ Unknown Home Child Resides: □ Parent/Family Member □ Foster Care □ Chronic care facility Caregiver(s): Single parent □ Single Parent □ □ Institutional (Check only one) extended Family □ Two Parents □ Two parent extended family Primary Caregiver Some high school □ □ Some college/university Education: or less (Check only one) High school □ □ College /university degree degree/GED □ Not applicable □ Unknown Caregiver(s) Primary Language: □ English □ Spanish □ Other: ______

SECTION C: SUPPORT AFTER DISCHARGE

Support After NICU Discharge: □ Yes □ No □ Unsure If Yes, Check all that apply □ 1. Tracheostomy □ 4. Gastrostomy □ 2. Ventilator □ 5. Nasogastric Feeds □ 3. Oxygen □ 6. Apnea or Cardio Respiratory Monitor

62 SECTION D: MEDICAL HOSPITALIZATION & SURGERIES Medical Hospitalization After NICU Discharge: □ Yes □ No □ Unsure If Yes, Category: Number of Number of Check all that apply Admissions Admissions □ 1. Respiratory Illness __ __ □ 5. Infections (not respiratory __ __ of shunt infections): □ 2. Nutrition/Failure to Thrive __ __ □ a. Meningitis __ __ □ 3. Seizure Complications __ __ □ b. Urinary Tract Infection __ __ □ 4. Shunt Complication __ __ □ c. Gastrointestinal Infection __ __ □ d. Other Infection __ __ (Specify)______□ 6. Other Medical Hospitalizations: (Specify)______

Surgical Procedures After NICU Discharge: □ Yes □ No □ Unsure Number of Procedures (P-Codes) ______

SURGICAL PROCEDURE CODES (P-CODES) CODE PROCEDURE Central Nervous System P-101 Shunt or shunt revision for hydrocephalus P-102 Other neurosurgical procedure Congenital Heart Defect Surgery P-201 Cardiac surgery Gastrointestinal Surgery P-301 Gastrostomy tube P-302 Inguinal hernia repair P-303 Other gastrointestinal surgical procedure Genitourinary Surgery P-401 Circumcision P-402 Other genitourinary surgical procedure Otolaryngology P-501 Tracheostomy P-502 Tympanostomy tubes P-503 Other ENT surgical procedures Ophthalmologic Surgery P-601 Retinal cryosurgery or laser surgery: single eye P-602 Retinal cryosurgery or laser surgery: both eye P-603 Strabismus surgery P-604 Other ophthalmological surgical procedure P-900 Other Surgical Procedures

63 Appendix 3c: UMass Memorial Medical Center Developmental Status Report (VON: 16 to 26 months)

Center Number: ______Center Name: ______Network ID Year of Birth: Date Last Seen: ______/___/_____ Number: (YYYY) (MM/DD/YYYY)

SECTION A: GROWTH PARAMETERS Corrected Age Growth Parameters Were Obtained

(months/days): __ __ months __ __ days Weight: __ __ . __ __ kg Head __ __ . __ __ cm Circumference: Height: __ __ . __ __ cm or __ __ . __ __ in Early Intervention Received: □ Yes □ No

64 SECTION E: DEVELOPMENTAL TESTING Bayley Scales of Infant Development: □ Completed □ Partly Completed □ Not Performed If completed or partially completed, a. Corrected age used in scoring: __ __ months __ __ days b. Results: Check all sections that apply. BSID-II □ MDI: Raw Score: ______Index Score for Corrected Age: ______BSID-II □ PDI: Raw Score: ______Index Score for Corrected Age: ______BSID-III Scaled □ Cognitive: Score: ______Composite Score: ______BSID-III Sum Scaled □ Language: Score: ______Composite Score: ______BSID-III Sum Scaled □ Motor: Score: ______Composite Score: ______

Mullen: Age Gains from Equivalent Descriptive Category last visit Domain (months) (months) very below above very GM __ __ □ □ □ average □ □ __ __ low average average high very below □ above very VR __ __ □ □ □ average □ __ __ low average average high very below □ above very FM __ __ □ □ □ average □ __ __ low average average high very below □ above very RL __ __ □ □ □ average □ __ __ low average average high very below □ above very EL __ __ □ □ □ average □ __ __ low average average high

ADOS: □ No BINS: □ L □ ASC □ M □ AC □ H IF partly completed or not performed, Check why: □ Neurosensory impairment (blind or deaf) □ Too severely delayed □ Uncooperative □ Other reason: ______Other Developmental Test Performed: □ Yes □ No If Yes, Abnormal results: □ Yes □ No

SECTION F: OVERALL CLINICAL APPRAISAL Clinical Cognitive Normal Suspect Impaired Appraisal: Function: □ □ □ Language: □ Normal □ Suspect □ Impaired Motor Function: □ Normal □ Suspect □ Impaired

65 Appendix 3d: UMass Memorial Medical Center Health Status Report (VON: 16 to 26 months)

Center Number: ______Center Name: ______Year of Birth Date Last Seen Network ID Number: ______/___/_____ (YYYY): (MM/DD/YYYY)

Birth Weight (g): □ <1000 □ 1000-1250 □ 1251-2000 □ 2001-2500 □ >2500 Gestational Age (weeks): □ <28 □ 28 – 38 □ 30 1/7-34 □ 34 1/7 -36 6/7 □ 37 – 42 □ >42

SECTION A: HEALTH STATUS Status at 18-24 Months Corrected Age: □ Alive □ Expired □ Unknown Consent Obtained at the Follow-Up-Visit: □ Yes □ No Corrected Age at the Follow-Up Visit: __ __ months __ __ days (months/days)

SECTION B: LIVING SITUATION Maternal Age at Infant Birth: __ __ Years □ Unknown Home Child Resides: □ Parent/Family Member □ Foster Care □ Chronic care facility Caregiver(s): Single parent □ Single Parent □ □ Institutional (Check only one) extended Family □ Two Parents □ Two parent extended family Primary Caregiver □ Some high school or less □ Some college/university Education: (Check only one) □ High school degree/GED □ College /university degree □ Not applicable □ Unknown Caregiver(s) Primary Language: □ English □ Spanish □ Other: ______

SECTION C: SUPPORT AFTER DISCHARGE

SECTION D: MEDICAL HOSPITALIZATION & SURGERIES

66 Medical re-hospitalization after ultimate discharge: □ Yes □ No □ Unsure If Yes, Category: Number of Number of Check all that apply Admissions Admissions □ 1. Respiratory Illness __ __ □ 5. Infections (not respiratory __ __ of shunt infections): □ 2. Nutrition/Failure to Thrive __ __ □ a. Meningitis __ __ □ 3. Seizure Complications __ __ □ b. Urinary Tract Infection __ __ □ 4. Shunt Complication __ __ □ c. Gastrointestinal Infection __ __ □ d. Other Infection __ __ (Specify)______□ 6. Other Medical Hospitalizations: (Specify)______

Surgical procedures after discharge: □ Yes □ No □ Unsure Number of Procedures (P-Codes) ______SURGICAL PROCEDURE CODES (P-CODES)

CODE PROCEDURE Central Nervous System P-101 Shunt or shunt revision for hydrocephalus P-102 Other neurosurgical procedure Congenital Heart Defect Surgery P-201 Cardiac surgery Gastrointestinal Surgery P-301 Gastrostomy tube P-302 Inguinal hernia repair P-303 Other gastrointestinal surgical procedure Genitourinary Surgery P-401 Circumcision P-402 Other genitourinary surgical procedure Otolaryngology P-501 Tracheostomy P-502 Tympanostomy tubes P-503 Other ENT surgical procedures Ophthamologic Surgery P-601 Retinal cryosurgery or laser surgery: single eye P-602 Retinal cryosurgery or laser surgery: both eye P-603 Strabismus surgery P-604 Other ophthamological surgical procedure P-900 Other Surgical Procedures

67 Appendix 3e: UMass Memorial Medical Center Developmental Status Report (26-1/30 to 42 months)

Date Last Seen ___/___/_____ (MM/DD/YYYY)

SECTION A: GROWTH PARAMETERS Corrected Age Growth Parameters Were Obtained

(months/days): __ __ months __ __ days Weight: __ __ . __ __ kg Head __ __ . __ __ cm Circumference: Height: __ __ . __ __ cm or __ __ . __ __ in Early Intervention Received: □ Yes □ No

68 SECTION E: DEVELOPMENTAL TESTING Bayley Scales of Infant Development: □ Completed □ Partly Completed □ Not Performed If completed or partially completed: a. Corrected age used in scoring: __ __ months __ __ days b. Results: Check and complete all sections that apply: BSID-II □ MDI: Raw Score: ______Index Score for Corrected Age: ______BSID-II □ PDI: Raw Score: ______Index Score for Corrected Age: ______BSID-III Scaled □ Cognitive: Score: ______Composite Score: ______BSID-III Sum Scaled □ Language: Score: ______Composite Score: ______BSID-III Sum Scaled □ Motor: Score: ______Composite Score: ______

ADOS: □ No module □ 1 □ 3 □ ASC □ 2 □ 4 □ AC IF partly completed or not performed check why: Check why: □ Neurosensory impairment (blind or deaf) □ Too severely delayed □ Uncooperative □ Other reason: ______Other Developmental Test Performed: □ Yes □ No If Yes, Abnormal results: □ Yes □ No

69 Appendix 3f: UMass Memorial Medical Center Health Status Report (26-1/30 months and older)

Date Last Seen ___/___/_____ (MM/DD/YYYY)

Birth Weight (g): □ <1000 □ 1000-1250 □ 1251-2000 □ 2001-2500 □ >2500 Gestational Age (weeks): □ <28 □ 28 – 38 □ 30 1/7-34 □ 34 1/7 -36 6/7 □ 37 – 42 □ >42

SECTION A: HEALTH STATUS Corrected Age at the Follow-Up Visit: __ __ months __ __ days (months/days)

SECTION B: LIVING SITUATION Maternal Age at Infant Birth: __ __ Years □ Unknown Chronic care Home Child Resides: □ Parent/Family Member □ Foster Care □ facility Caregiver(s): Single parent □ Single Parent □ □ Institutional (Check only one) extended Family □ Two Parents □ Tw0 parent extended family Primary Caregiver □ Some high school or less □ Some college/university Education: (Check only one) □ High school degree/GED □ College /university degree □ Not applicable □ Unknown Caregiver(s) Primary Language: □ English □ Spanish □ Other: ______

SECTION C: SUPPORT AFTER DISCHARGE

70 SECTION D: MEDICAL HOSPITALIZATION & SURGERIES Medical re-hospitalization since last seen: □ Yes □ No □ Unsure If Yes, Category: Check all that Number of Number of apply Admissions Admissions □ 1. Respiratory Illness __ __ □ 5. Infections (not respiratory __ __ of shunt infections): □ 2. Nutrition/Failure to Thrive __ __ □ a. Meningitis __ __ □ 3. Seizure Complications __ __ □ b. Urinary Tract Infection __ __ □ 4. Shunt Complication __ __ □ c. Gastrointestinal Infection __ __ □ d. Other Infection __ __ (Specify)______□ 6. Other Medical Hospitalizations: (Specify)______

Surgical procedures since last seen: □ Yes □ No □ Unsure Number of Procedures (P-Codes) ______

71 Appendix 3g: UMass Memorial Medical Center Developmental Status Report (42.1 months and older)

Date Last Seen ___/___/_____ (MM/DD/YYYY)

SECTION A: GROWTH PARAMETERS Corrected Age Growth Parameters Were Obtained

(months/days): __ __ months __ __ days Weight: __ __ . __ __ kg Head __ __ . __ __ cm Circumference: Height: __ __ . __ __ cm or __ __ . ____ in Early Intervention Received: □ Yes □ No

72 SECTION E: DEVELOPMENTAL TESTING

ADOS: □ No module □ 1 □ 3 □ ASC □ 2 □ 4 □ AC KBIT-2: ______V (verbal) ______N (non-verbal) WRAT: ______WR (word reading) SC (sentence ______comprehension) ______S (spelling) Einstein: □ A (Acceptable) □ U (Unacceptable)

IF partly completed or not performed, check why: □ Neurosensory impairment (blind or deaf) □ Too severely delayed □ Uncooperative □ Other reason: ______Other Developmental Test Performed: □ Yes □ No If Yes, Abnormal results: □ Yes □ No